Benzofuran-2-sulfonamides derivatives as chemokine receptor modulators

ABSTRACT

The present invention relates to novel benzofuran-2-sulfonamide derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of chemokine receptors.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.13/782,159 filed on Mar. 1, 2013 which in turn claims the benefit ofU.S. Provisional Application Ser. No. 61/605,300, filed Mar. 1, 2012,each which is incorporated herein by reference in their entirety andserve as the basis for a priority and/or benefit claim.

FIELD OF THE INVENTION

The present invention relates to novel benzofuran-2-sulfonamidederivatives, processes for preparing them, pharmaceutical compositionscontaining them and their use as pharmaceuticals as modulators ofchemokine receptors. The invention relates specifically to the use ofthese compounds and their pharmaceutical compositions to treat disordersassociated with chemokine receptor modulation.

BACKGROUND OF THE INVENTION

Chemokines are a group of 7- to 14-kd peptides that play an importantrole in orchestrating leukocyte recruitment and migration duringinflammation, and therefore represent an important target foranti-inflammatory therapies (Wells et al., 2006). They act by binding toseven-transmembrane, G protein-coupled receptors, the chemokinereceptors. The chemokine system is complex, with about 50 chemokines and20 chemokine receptors identified in humans, often acting withredundancy, making selection of specific antagonists difficult (Gerardand Rollins, 2001). Genetic knockout strategies have confirmed theimportance of chemokines as regulators of immune function, but thedeletion of specific chemokines has led to only specific and relativelymild defects in the inflammatory response further emphasizing thecomplex redundancy of the system. Selectivity is crucial for use ofchemokine receptor antagonists in systemic diseases where a singlechemokine-receptor system is implicated such as atheroscelorsis wherethe macrophage/monocyte system is the major player in order to allow asubtle and specific control over immune function (Weisberg et al., 2006;Feria and Diaz Gonzalez et al., 2006).

Many ocular conditions are characterized by inappropriate migration andinfiltration of cells such as leukocytes and endothelial cells into theeye with deleterious effects to ocular structures (Wallace et al.,2004). Chemokines have been identified in such diseases andmisregulation of the chemokine system is apparent in corneal graftrejection, diabetic retinopathy, age-related macular degeneration(ARMD), chronic inflammatory diseases such as uveitis, dry eye etc. Micelacking CCR2 or MCP-1 develop features of ARMD with age, includingdrusen deposits, choroidal neovascularization and photoreceptor atrophyindicating a crucial role for this chemokine and its receptor signaling(Amabati et al., 2003). Thus CCR2 receptor-specific inhibitor might havepotential therapeutic benefit in ocular diseases like ARMD. In contrast,various human and animal studies have identified several chemokines indifferent forms of uveitis, produced both by resident and infiltratingcells, that strongly suggests a prominent role for these molecules inits pathogenesis. Studies in rat and mice models of uveitis havedemonstrated up-regulation of monocyte chemoattractant protein-1(MCP-1), macrophage inflammatory protein-1 (MIP-1), RANTES, stromalderived factor-1 (SDF-1) which are powerful chemoattractants formonocytes and T-cells (Fang et al., 2004; Keino et al., 2003). Similarfindings have been reported in peripheral blood mononuclear cells inpatients with acute anterior uveitis (AAU), the most common form ofhuman uveitis (Klitgaard et al., 2004). MCP-1 knockout mice and CCR5knockout mice show reduced endotoxin-induced uveitis, which is theanimal model for AAU (Takeuchi et al., 2005; Tuallion et al., 2002). Ithas also been demonstrated that blocking the chemokine system upstreamwith the use of NF-κB blockers significantly attenuates experimental AAUin rats (Yang et al., 2005). Blockage of NF-κB results intranscriptional inhibition of multiple chemokines. Given the complexityof pathogenesis in uveitis it is unlikely that a selective inhibition ofa chemokine receptor in monotherapy will offer therapeutic benefit. Asimilar role of multiple chemokines have been shown to be correlatedwith clinical stage of disease in diabetic retinopathy and dry eye(Meleth et al., 2005; Yamagami et al., 2005). In these ocular diseasesthe use of broad spectrum chemokine receptor inhibitor which inhibitsthe function of a wide range of chemokines may be beneficial.

The first broad spectrum chemokine inhibitor (BSCI) to be reported wastermed Peptide 3, which was derived from the sequence of human chemokineMCP-1 and was shown to block the migration of monocytes in response toMCP-1, MIP-1, RANTES and SDF-1 (Reckless and Grainger. 1999). A cyclicretro inverse analogue of Peptide 3, constructed of D-amino acids in thereverse sequence, called NR58-3.14.3 was observed to be a more potentchemokine inhibitor (Beech et al., 2001). NR58-3.14.3 has been used totest for anti-inflammatory activities in animal models ofatherosclerosis, lung inflammation, irritable bowel syndrome etc (Beechet al., 2001; Grainger and Reckless. 2003; Tokuyama et al., 2005).However there are several disadvantages to using these BSCI as along-term therapeutic strategy. The known BSCIs which are peptides whichhave relatively low potency, poor pharmacokinetics, and are unstable invivo. In addition, systemic use of broad spectrum chemokine receptorinhibitors could potentially lead to deleterious side effects due totheir systemic anti-inflammatory activity. However in ocular diseases, alocal or topical application would prevent the broad spectrum inhibitorto be taken up systemically. Identification of a small moleculeinhibitor of several chemokine receptors could be very useful fortreatment of inflammatory ocular diseases. Given the evidence for therole of multiple chemokines in several ocular diseases and theseresults, we propose that the use of small and large molecule broadspectrum chemokine receptor inhibitors will have utility in the localtreatment of ocular inflammatory diseases including, but not limited to,uveitis, dry eye, diabetic retinopathy, allergic eye disease andproliferative retinopathies. Manipulation of multiple chemokinestherefore represents a novel therapeutic approach in treating oculardiseases.

WO2008008374 discloses CCR2 inhibitors and methods of use thereof.

WO03/099773 discloses CCR9 inhibitors and methods of use thereof.

US2012014997 discloses CCR9 inhibitors and methods of use thereof.

U.S. Pat. No. 7,622,583 discloses heteroaryl sulfonamides as antagonistsof the CCR2 receptor.

US20110118248 discloses heteroaryl sulfonamides as antagonists of theCCR2 receptor.

U.S. Pat. No. 7,884,110 discloses CCR2 inhibitors and methods of usethereof.

US 2008/0293720 discloses pyridinyl sulfonamide modulators of chemokinereceptors.

U.S. Pat. No. 7,393,873 discloses arylsulfonamide derivatives.

SUMMARY OF THE INVENTION

A group of novel benzofuran-2-sulfonamide derivatives which are potentand selective chemokine receptor modulators, has been now discovered. Assuch, the compounds described herein are useful in treating a widevariety of disorders associated with modulation of chemokine receptors.The term “modulator” as used herein, includes but is not limited to:receptor agonist, antagonist, inverse agonist, inverse antagonist,partial agonist, partial antagonist.

This invention describes compounds of Formula I, which have chemokinereceptor biological activity. The compounds in accordance with thepresent invention are thus of use in medicine, for example in thetreatment of humans with diseases and conditions that are alleviated bychemokine receptor modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the individual geometrical isomers, enantiomers,diastereoisomers, tautomers, zwitterions and pharmaceutically acceptablesalts thereof:

wherein:

-   -   R¹ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R² is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R³ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁴ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁵ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is halogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is O, C(O), S, S(O), S(O)₂, or —C(═NOR¹⁶)—;    -   a is 0 or 1;    -   R¹¹ is CN, substituted or unsubstituted C₁₋₆ alkyl, CF₃, OR¹²,        NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₂₋₆ alkyne,        substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can form an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can form an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   R¹⁶ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   X is CR¹⁷;    -   R¹⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl; with        the provisos:    -   a). when R⁹ is S, S(O) or S(O)₂ then R¹¹ is substituted or        unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted        heterocycle, or substituted or unsubstituted C₃₋₈ cycloalkyl;        and    -   the compound of Formula I is not of structure:

In another aspect the invention provides a compound having Formula Iwherein:

-   -   R¹ is hydrogen;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is halogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is S, S(O) or S(O)₂;    -   a is 1;    -   R¹¹ is substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   R¹⁶ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   X is CR¹⁷;    -   R¹⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.        In another aspect the invention provides a compound having        Formula I wherein:    -   R¹ is hydrogen;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is halogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        OR¹²NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is O or C(O);    -   a is 1;    -   R¹¹ is CN, substituted or unsubstituted C₁₋₆ alkyl, CF₃, OR¹²,        NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₂₋₆ alkyne,        substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can form an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can form an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   R¹⁶ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   X is CR¹⁷;    -   R¹⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.        In another aspect the invention provides a compound having        Formula I wherein:    -   R¹ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R² is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R³ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁴ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁵ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁶ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁷ is halogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R⁸ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁹ is S, S(O) or S(O)₂    -   a is 1;    -   R¹¹ is substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle or substituted or unsubstituted C₃₋₈        cycloalkyl;    -   X is CR¹⁷;    -   R¹⁷ is hydrogen; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.        In another aspect the invention provides a compound having        Formula I wherein:    -   R¹ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R² is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R³ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁴ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁵ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁶ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁷ is halogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R⁸ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁹ is O;    -   a is 1;    -   R¹¹ is CN, substituted or unsubstituted C₁₋₆ alkyl, CF₃, OR¹²,        NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₂₋₆ alkyne,        substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can form an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can form an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   X is CR¹⁷;    -   R¹⁷ is hydrogen; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.        In another aspect the invention provides a compound having        Formula I wherein:    -   R¹ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R² is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R³ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁴ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁵ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁶ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁷ is halogen;    -   R⁸ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁹ is C(O);    -   a is 1;    -   R¹¹ is CN, substituted or unsubstituted C₁₋₆ alkyl, CF₃, OR¹²,        NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₂₋₆ alkyne,        substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can form an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can form an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   X is CR¹⁷;    -   R¹⁷ is hydrogen; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.        In another aspect the invention provides a compound having        Formula I wherein:    -   R¹ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R² is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R³ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁴ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁵ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁶ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁷ is halogen;    -   R⁸ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁹ is —C(═NOR¹⁶)—;    -   a is 1;    -   R¹¹ is CN, substituted or unsubstituted C₁₋₆ alkyl, CF₃, OR¹²,        NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl, substituted or unsubstituted C₂₋₆ alkyne,        substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can form an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can form an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   R¹⁶ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   X is CR¹⁷;    -   R¹⁷ is hydrogen; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 6 carbon atoms. One methylene(—CH₂—) group, of the alkyl can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₆cycloalkyl. Hydrogen atoms on alkyl groups can be substituted by groupsincluding, but not limited to: halogens, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, —OC₁₋₆ alkyl, —NH₂,—NO₂, amides, carboxylic acids, ketones, ethers, esters, aldehydes, orsulfonamides.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by groups including, but not limited to:halogens, —OH, C₃₋₈ cycloalkyl, non-aromatic heterocycles, aromaticheterocycles, —OC₁₋₆ alkyl, —NH₂, —NO₂, amides, ethers, esters,carboxylic acids, aldehydes, ketones, or sulfonamides.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturatedcycloalkyl having one or more double bonds. Cycloalkenyl groups can bemonocyclic or polycyclic.

Cycloalkenyl groups can be substituted by groups including, but notlimited to: halogens, —OH, C₃₋₈ cycloalkyl, non-aromatic heterocycles,aromatic heterocycles, —OC₁₋₆ alkyl, —NH₂, —NO₂, amides, ethers, esters,aldehydes, ketones, carboxylic acids, sulfonamides groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by C₁₋₆ alkyl.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected from O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be interrupted by a C═O; the Sheteroatom can be oxidized. Heterocycles can be monocyclic orpolycyclic. Heterocyclic ring moieties can be substituted by groupsincluding, but not limited to: halogens, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, —OC₁₋₆ alkyl, —NH₂,—NO₂, amides, ethers, esters, aldehydes, carboxylic acids, ketones,sulfonamides groups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryl can be monocyclic or polycyclic.Aryl can be substituted by groups including, but not limited to:halogens, —OH, C₃₋₈ cycloalkyl, non-aromatic heterocycles, aromaticheterocycles, —OC₁₋₆ alkyl, —NH₂, —NO₂, amides, ethers, esters,carboxylic acids, ketones, aldehydes, sulfonamides groups.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y)” or wherein R^(x) and R^(y) are the same orindependently H or C₁₋₆ alkyl.

The term “ketone” as used herein, represents a group of formula“—C(O)R^(x)” wherein R^(x) is C₁₋₆ alkyl.

The term “ester” as used herein, represents a group of formula“—C(O)OR^(x)” wherein R^(x) is C₁₋₆ alkyl.

The term “ether” as used herein, represents a group of formula “—OR^(x)”wherein R^(x) is C₁₋₆ alkyl.

The term “aldehyde” as used herein, represents a group of formula“—C(O)H”.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) are the same orindependently H or C₁₋₆ alkyl.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “amino” as used herein, represents a group of formula “—NH₂”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” or the term “sulfone” as used herein, represents agroup of formula “—SO₂—”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—O—P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom

Compounds of the invention are:

-   N-(5-chloro-2-methoxyphenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-methylphenyl)-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(trifluoromethoxy)phenyl]-1-benzofuran-2-sulfonamide;-   methyl 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorobenzoate;-   N-(5-chloro-2-ethoxyphenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-ethynylphenyl)-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(4-oxopiperidin-1-yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(morpholin-4-ylcarbonyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(2-methylpyridin-3-yl)oxy]phenyl}-1-benzofuran-2-sulfonamide;-   methyl    2-{2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}benzoate;-   2-{2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}benzoic    acid;-   N-[5-chloro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;-   2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chloro-N-phenylbenzamide;-   N-(5-chloro-2-cyanophenyl)-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylacetyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1Z)-N-methoxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1Z)-N-hydroxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-[2-(benzyloxy)-5-chlorophenyl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylethynyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(2-phenylethyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(Z)-2-phenylethenyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-[5-methyl-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-methyl-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-methyl-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-fluoro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-fluoro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-fluoro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;-   methyl    2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoate;-   2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoic    acid;-   2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic    acid;-   3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic    acid;-   4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic    acid;-   methyl    3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoate;-   3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoic    acid;-   methyl    2-(2-{2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}ethyl)benzoate;-   2-(2-{2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}ethyl)benzoic    acid.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalicacid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoicacid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic,benzenesulfonic, formic acid and the like (Handbook of PharmaceuticalSalts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag HelveticaChemica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds),Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the chemokine receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of chemokine receptors.Such methods can be performed, for example, by administering to asubject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated bychemokine receptor modulation.

Therapeutic utilities of chemokine receptor modulators are skininflammatory diseases and conditions, including, but are not limited to:rosacea (dilation of the blood vessels just under the skin), sunburn,chronic sun damage, discreet erythemas, psoriasis, atopic dermatitis,menopause-associated hot flashes, hot flashes resulting fromorchiectomyatopic dermatitis, photoaging, seborrheic dermatitis, acne,allergic dermatitis, irritant dermatitis, telangiectasia (dilations ofpreviously existing small blood vessels) of the face, rhinophyma(hypertrophy of the nose with follicular dilation), red bulbous nose,acne-like skin eruptions (may ooze or crust), burning or stingingsensation of the face, irritated and bloodshot and watery eyes,cutaneous hyperactivity with dilation of blood vessels of the skin,Lyell's syndrome, Stevens-Johnson syndrome, erythema multiforme minor,erythema multiforme major and other inflammatory skin diseases, actinickeratoses, arsenic keratoses, inflammatory and non-inflammatory acne,ichthyoses and other keratinization and hyperproliferative disorders ofthe skin, eczema, wound healing.

Therapeutic utilities of chemokine receptor modulators are ocularinflammatory diseases including, but not limited to, uveitis, dry eye,keratitis, allergic eye disease and conditions affecting the posteriorpart of the eye, such as maculopathies and retinal degenerationincluding non-exudative age related macular degeneration, exudative agerelated macular degeneration, choroidal neovascularization, diabeticretinopathy, acute macular neuroretinopathy, central serouschorioretinopathy, cystoid macular edema, and diabetic macular edema;uveitis, retinitis, and choroiditis such as acute multifocal placoidpigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy,infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediateuveitis (pars planitis), multifocal choroiditis, multiple evanescentwhite dot syndrome (mewds), ocular sarcoidosis, posterior scleritis,serpiginous choroiditis, subretinal fibrosis and uveitis syndrome,Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/exudative diseasessuch as retinal arterial occlusive disease, central retinal veinocclusion, disseminated intravascular coagulopathy, branch retinal veinocclusion, hypertensive fundus changes, ocular ischemic syndrome,retinal arterial microaneurysms, Coat's disease, parafovealtelangiectasis, hemi-retinal vein occlusion, papillophlebitis, centralretinal artery occlusion, branch retinal artery occlusion, carotidartery disease (CAD), frosted branch angiitis, sickle cell retinopathyand other hemoglobinopathies, angioid streaks, familial exudativevitreoretinopathy, and Eales disease; traumatic/surgical conditions suchas sympathetic ophthalmia, uveitic retinal disease, retinal detachment,trauma, conditions caused by laser, conditions caused by photodynamictherapy, photocoagulation, hypoperfusion during surgery, radiationretinopathy, and bone marrow transplant retinopathy; proliferativedisorders such as proliferative vitreal retinopathy and epiretinalmembranes, and proliferative diabetic retinopathy; infectious disorderssuch as ocular histoplasmosis, ocular toxocariasis, presumed ocularhistoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinaldiseases associated with HIV infection, choroidal disease associate withHIV infection, uveitic disease associate with HIV infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis; genetic disorders suchas retinitis pigmentosa, systemic disorders with accosiated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Best's disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/holessuch as retinal detachment, macular hole, and giant retinal tear; tumorssuch as retinal disease associated with tumors, congenital hypertrophyof the retinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of chemokinereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a therapeutically effective amount of atleast one compound of the invention, or any combination thereof, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms andindividual isomers, enantiomers, and diastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of ocular inflammatory diseases including,but not limited to, uveitis, dry eye, Keratitis, allergic eye diseaseand conditions affecting the posterior part of the eye, such asmaculopathies and retinal degeneration including non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy, acutemacular neuroretinopathy, central serous chorioretinopathy, cystoidmacular edema, and diabetic macular edema; uveitis, retinitis, andchoroiditis such as acute multifocal placoid pigment epitheliopathy,Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis,lyme, tuberculosis, toxoplasmosis), intermediate uveitis (parsplanitis), multifocal choroiditis, multiple evanescent white dotsyndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginouschoroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-andHarada syndrome; vasuclar diseases/exudative diseases such as retinalarterial occlusive disease, central retinal vein occlusion, disseminatedintravascular coagulopathy, branch retinal vein occlusion, hypertensivefundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser, conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (PONS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with accosiated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds and their pharmaceutically-acceptable salts may beadministered through different routes, including but not limited totopical eye drops, direct injection, application at the back of the eyeor formulations that may further enhance the long duration of actionssuch as a slow releasing pellet, suspension, gel, or sustained deliverydevices such as any suitable drug delivery system (DDS) known in theart. While topical administration is preferred, this compound may alsobe used in an intraocular implant as described in U.S. Pat. No.7,931,909.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists of chemokine receptors.Thus, in further embodiments of the invention, there are providedmethods for treating a disorder associated with modulation of chemokinereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one invention compound. Asused herein, the term “therapeutically effective amount” means theamount of the pharmaceutical composition that will elicit the biologicalor medical response of a subject in need thereof that is being sought bythe researcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The described benzofuran-2-sulfonamide derivatives wereprepared by methods as shown in Scheme 1. Those skilled in the art willbe able to routinely modify and/or adapt Scheme 1 to synthesize anycompounds of the invention covered by Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 12.0 and someintermediates' and reagents' names used in the examples were generatedwith software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000from MDL ISIS Draw 2.5 SP1. In general, characterization of thecompounds is performed according to the following methods:

NMR spectra are recorded on Varian 600 or Varian 300, in the indicatedsolvent at ambient temperature; chemical shifts in [ppm], couplingconstants in [Hz].

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates were preparedaccording to published procedures. Solvents were purchased fromcommercial sources in appropriate quality and used as received. Airand/or moisture-sensitive reactions were run under an Ar— or N₂—atmosphere.

Usually the compounds of the invention were purified by chromatography:CombiFlash Companion and RediSep Rf silica gel 60 (0.04-0.063 mm);Preparative thin layer chromatography (PTLC): Analtech (silica gel 60F₂₅₄, 500 or 1000 μm).

The following abbreviations are used in the examples:

-   CH₂Cl₂ dichloromethane-   NaOH sodium hydroxide-   MeOH methanol-   CD₃OD deuterated methanol-   HCl hydrochloric acid-   HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate)-   CuI copper iodide-   DMF dimethylformamide-   EtOAc ethyl acetate-   CDCl₃ deuterated chloroform-   CHCl₃ chloroform-   DMSO-d₆ deuterated dimethyl sulfoxide-   THF tetrahydrofuran-   K₂CO₃ potassium carbonate-   N₂ nitrogen-   Et₃N triethylamine-   Na₂SO₄ sodium sulfate-   Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) dichloride-   iPr₂NEt N,N′-diisopropylethylamine-   EDC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   MPLC medium pressure liquid chromatography-   NH₄Cl Ammonium chloride-   DMAP N,N-Dimethylpyridin-4-amine-   mCPBA 3-Chloroperoxybenzoic add-   SeO₂ Selenium dioxide-   KOH potassium hydroxide-   Et₂O diethylether-   LiBr lithium bromide-   K₂CO₃ potassium carbonate-   TMSCHN₂ trimethylsilyldiazomethane

EXAMPLE 1 Compound 1N-(5-Chloro-2-methoxyphenyl)benzofuran-2-sulfonamide

To a solution of 5-chloro-2-methoxyaniline (100 mg, 0.63 mmol) inpyridine (1 ml) at room temperature was added benzofuran-2-sulfonylchloride (137 mg, 0.63 mmol) and the reaction was stirred during 64hours and then was concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (25% EtOAc in hexanes) toyield Compound 1 as a light yellow solid (194 mg, 91%).

¹H NMR (CHLOROFORM-d) δ: 7.65 (d, J=7.9 Hz, 1H), 7.59 (d, J=2.3 Hz, 1H),7.53 (d, J=8.2 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.39 (d, J=0.9 Hz, 1H),7.30-7.34 (m, 2H), 7.02 (dd, J=8.8, 2.3 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H),3.68 (s, 3H).

EXAMPLE 2 Compound 2N-(5-Chloro-2-methylphenyl)-1-benzofuran-2-sulfonamide

To a solution of 5-chloro-2-methylaniline (50 μl, 0.62 mmol) in pyridine(1 ml) at room temperature was added benzofuran-2-sulfonyl chloride (135mg, 0.62 mmol) and the reaction was stirred during 64 hours and wasconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (20% EtOAc in hexanes) to yield Compound 2as a white solid (177 mg, 89%).

¹H NMR (CHLOROFORM-d) δ: 7.64 (d, J=7.9 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H),7.47 (ddd, J=8.4, 7.3, 1.3 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.31-7.36(m, 2H), 7.00-7.07 (m, 2H), 6.63-6.77 (m, 1H), 2.14 (s, 3H).

EXAMPLE 3 Compound 3N-[5-Chloro-2-(trifluoromethoxy)phenyl]-1-benzofuran-2-sulfonamide

To a solution of 5-chloro-2-(trifluoromethoxy)aniline (106 mg, 0.50mmol) in pyridine (1 ml) at room temperature was addedbenzofuran-2-sulfonyl chloride (109 mg, 0.50 mmol) and the reaction wasstirred during 72 hours and was concentrated in vacuo. The residue wastreated with 4M NaOH (1 ml) in MeOH (3 ml) at room temperature for 30minutes, acidified with 6M HCl, diluted with brine, and was extractedwith EtOAc. The organic layer was dried over Na₂SO₄, and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (10% EtOAc in hexanes) to yield Compound 3 as an off-white solid (76mg, 39%).

¹H NMR (CHLOROFORM-d) δ: 7.75 (d, J=2.1 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H),7.50-7.53 (m, 1H), 7.44-7.49 (m, 2H), 7.32 (t, J=7.2 Hz, 1H), 7.07-7.12(m, 2H).

EXAMPLE 4 Compound 4 Methyl2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorobenzoate

To a solution of methyl 2-amino-4-chlorobenzoate (93 mg, 0.50 mmol) inpyridine (1 ml) at room temperature was added benzofuran-2-sulfonylchloride (109 mg, 0.50 mmol) and the reaction was stirred for 72 hoursand was concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (10% EtOAc in hexanes) to yield Compound 4as a white solid (101 mg, 55%).

¹H NMR (CHLOROFORM-d) δ: 11.13 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.84 (s,1H), 7.69 (d, J=8.5 Hz, 1H), 7.51-7.55 (m, 2H), 7.46 (t, J=7.9 Hz, 1H),7.31-7.36 (m, 1H), 7.05 (dd, J=8.5, 2.1 Hz, 1H), 3.92 (s, 3H).

EXAMPLE 5 Compound 5N-(5-Chloro-2-ethoxyphenyl)-1-benzofuran-2-sulfonamide

To a solution of 5-chloro-2-ethoxyaniline (148 mg, 0.86 mmol) inpyridine (2 ml) benzofuran-2-sulfonyl chloride (189 mg, 0.86 mmol) wasadded at room temperature and the reaction was stirred for 16 hours andwas concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (10-20% EtOAc in hexanes) to yield Compound5 as an off-white solid (229 mg, 75%).

¹H NMR (CHLOROFORM-d) δ: 7.63 (d, J=7.9 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H),7.48-7.51 (m, 1H), 7.41-7.46 (m, 1H), 7.36 (s, 1H), 7.28-7.33 (m, 2H),6.98 (dd, J=8.7, 2.5 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.86 (q, J=6.8 Hz,2H), 1.26-1.31 (m, 3H).

EXAMPLE 6 Intermediate 1 5-Chloro-2-((trimethylsilyl)ethynyl)aniline

To a solution of 5-chloro-2-iodoaniline (1.50 g, 5.92 mmol) andethynyltrimethylsilane (1.25 ml, 8.88 mmol) in Et₃N (20 ml) was addedCuI (5.6 mg, 0.030 mmol) and Pd(PPh₃)₂Cl₂ (21 mg, 0.030 mmol) and themixture was stirred at room temperature for 5 hours. Celite was addedand the suspension was filtered, rinsed with EtOAc. The filtrate wasconcentrated in vacuo to yield Intermediate 1 as a yellow oil (1.32 g,100%).

¹H NMR (CHLOROFORM-d) δ: 7.20 (d, J=8.2 Hz, 1H), 6.69 (d, J=1.8 Hz, 1H),6.63 (dd, J=8.2, 2.1 Hz, 1H), 4.30 (br. s., 2H), 0.27 (s, 9H).

EXAMPLE 7 Intermediate 2N-(5-Chloro-2-((trimethylsilyl)ethynyl)phenyl)benzofuran-2-sulfonamide

To a solution of Intermediate 1 (1.32 g, 5.89 mmol) in pyridine (12 ml)was added benzofuran-2-sulfonyl chloride (1.53 g, 7.07 mmol) and thereaction was stirred at room temperature for 16 hours and wasconcentrated in vacuo. The residue was taken in EtOAc, washed with 1MHCl, brine, dried over Na₂SO₄, and concentrated in vacuo to yield crudeIntermediate 2 as a reddish brown solid (3.5 g). The crude product wasused in the next step without further purification.

EXAMPLE 8 Compound 6N-(5-Chloro-2-ethynylphenyl)-1-benzofuran-2-sulfonamide

To a solution of crude Intermediate 2 (3.43 g, 8.49 mmol) in MeOH (50ml) was added K₂CO₃ (2.45 g, 17.8 mmol) and the mixture was stirred atroom temperature for 16 hours. The solvent was removed, and the residuewas acidified, extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo. The crude productwas purified by flash column chromatography on silica gel (0-25% EtOAcin hexanes) to yield Compound 6 as a light brown solid (1.47 g, 75%).

1H NMR (CHLOROFORM-d) δ: 7.69 (d, J=2.1 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H),7.54 (dd, J=8.5, 0.9 Hz, 1H), 7.49 (dd, J=7.0, 1.2 Hz, 2H), 7.47 (d,J=0.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.05 (dd,J=8.2, 2.1 Hz, 1H), 3.47 (s, 1H).

EXAMPLE 9 Intermediate 3 1-(2-Amino-4-chlorobenzoyl)piperidin-4-one

To 2-amino-4-chlorobenzoic acid (0.86 g, 5.0 mmol) and piperidin-4-onehydrochloride (0.77 g, 5.0 mmol) in DMF (10 ml) was added HBTU (1.90 g,5.0 mmol) and iPr₂NEt (2.6 ml, 15 mmol). The mixture was stirred at roomtemperature for 16 hours, diluted with 1M NaOH, extracted with EtOAc.The organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by flash columnchromatography on silica gel (50-75% EtOAc in hexanes) to yieldIntermediate 3 as a light yellow solid (1.35 g, 100%).

1H NMR (acetone) δ: 7.18 (d, J=8.2 Hz, 1H), 6.86 (d, J=1.8 Hz, 1H), 6.64(dd, J=8.2, 2.1 Hz, 1H), 5.30 (br. s., 2H), 3.85 (t, J=6.2 Hz, 4H), 2.48(t, J=6.3 Hz, 4H).

EXAMPLE 10 Compound 7N-{5-Chloro-2-[(4-oxopiperidin-1-yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamide

To Intermediate 3 (90 mg, 0.36 mmol) in pyridine (1.5 ml) was addedbenzofuran-2-sulfonyl chloride (77 mg, 0.36 mmol) and the reaction wasstirred at room temperature for 6 hours and was concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(50-70% EtOAc in hexanes) followed by PTLC (50% EtOAc in hexanes) toyield Compound 7 (40 mg, 26%).

1H NMR (CHLOROFORM-d) δ: 8.97 (s, 1H), 7.82 (s, 1H), 7.67 (d, J=7.9 Hz,1H), 7.45-7.54 (m, 2H), 7.43 (s, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.17 (s,2H), 3.65 (br. s., 4H), 2.31 (br. s., 4H).

EXAMPLE 11 Intermediate 4 (2-Amino-4-chlorophenyl)(morpholino)methanone

To 2-amino-4-chlorobenzoic acid (1.72 g, 10.0 mmol) and morpholine (1.3ml, 15.0 mmol) in DMF (10 ml) was added EDC (2.30 g, 12.0 mmol). Themixture was stirred at room temperature for 16 hours, diluted with H₂O,extracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The crude product was purifiedby flash column chromatography on silica gel (50% EtOAc in hexanes) toyield Intermediate 4 as an off-white solid (2.14 g, 89%).

1H NMR (CHLOROFORM-d) δ: 7.00 (d, J=8.2 Hz, 1H), 6.66-6.75 (m, 2H), 4.49(br. s., 2H), 3.67-3.75 (m, 4H), 3.63 (d, J=5.0 Hz, 4H).

EXAMPLE 12 Compound 8N-[5-Chloro-2-(morpholin-4-ylcarbonyl)phenyl]-1-benzofuran-2-sulfonamide

To Intermediate 4 (120 mg, 0.50 mmol) in pyridine (2 ml) was addedbenzofuran-2-sulfonyl chloride (108 mg, 0.50 mmol) and the reaction wasstirred at room temperature for 6 hours and was concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(50-70% EtOAc in hexanes) followed by PTLC (60% EtOAc in hexanes) toyield Compound 8 as an off-white solid (133 mg, 63%).

EXAMPLE 13 Intermediate 5 3-(4-Chloro-2-nitrophenoxy)-2-methylpyridine

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (720 mg, 4.10 mmol) inDMF (10 ml) was added 2-methylpyridin-3-ol (448 mg, 4.10 mmol) and K₂CO₃(2.8 g, 20.5 mmol) and the reaction was stirred at 60° C. for 3 hours,diluted with H₂O, and the resulting solution was extracted with EtOAcand washed with brine, dried over Na₂SO₄ and concentrated in vacuo,followed by MPLC purification to yield Intermediate 5 as a yellow solid(1.03 g, 94%).

¹H NMR (600 MHz, acetone) δ 8.35 (d, J=4.70 Hz, 1H), 8.11 (d, J=2.64 Hz,1H), 7.71 (dd, J=2.49, 8.95 Hz, 1H), 7.40 (d, J=8.22 Hz, 1H), 7.27 (dd,J=4.70, 8.22 Hz, 1H), 7.11 (d, J=9.10 Hz, 1H), 2.45 (s, 3H).

EXAMPLE 14 Intermediate 6 5-Chloro-2-((2-methylpyridin-3-yl)oxy)aniline

To a solution of Intermediate 5 (1.03 g, 3.9 mmol) in MeOH (15 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (6.3 g, 98 mmol). Thesuspension was stirred at room temperature for 2 hour and was filtered,the filtrate was extracted with EtOAc (×2). The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The crudeIntermediate 6 (740 mg, 81%) was used in the next reaction withoutfurther purification.

¹H NMR (600 MHz, CD₃OD) δ 8.11 (d, J=4.99 Hz, 1H), 7.19 (dd, J=4.99,8.22 Hz, 1H), 7.09 (dd, J=1.17, 8.22 Hz, 1H), 6.88 (d, J=2.35 Hz, 1H),6.67 (d, J=8.51 Hz, 1H), 6.59 (dd, J=2.64, 8.51 Hz, 1H), 2.55 (s, 3H).

EXAMPLE 15 Compound 9N-{5-Chloro-2-[(2-methylpyridin-3-yl)oxy]phenyl}-1-benzofuran-2-sulfonamide

To Intermediate 6 (488 mg, 2.1 mmol) in pyridine (4 ml) was addedbenzofuran-2-sulfonyl chloride (450 mg, 2.1 mmol) and the reaction wasstirred at room temperature for 16 hours. Solvent was removed in vacuoand the crude product was purified by flash column chromatography onsilica gel (0-30% EtOAc in hexanes) followed by re-crystallization from20% EtOAc/Hexane to yield Compound 9 (553 mg, 64%) as a yellow solid.

¹H NMR (600 MHz, CD₃OD) δ 8.03 (dd, J=1.17, 4.70 Hz, 1H), 7.68 (d,J=7.92 Hz, 1H), 7.63 (d, J=2.64 Hz, 1H), 7.39-7.48 (m, 2H), 7.31-7.37(m, 2H), 7.15 (dd, J=2.64, 8.80 Hz, 1H), 6.87 (dd, J=4.69, 8.22 Hz, 1H),6.69 (dd, J=1.17, 8.22 Hz, 1H), 6.60 (d, J=8.51 Hz, 1H), 2.20 (s, 3H).

EXAMPLE 16 Intermediate 7 Methyl 2-(4-chloro-2-nitrophenoxy)benzoate

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (588 mg, 3.35 mmol) inDMF (10 ml) was added methyl 2-hydroxybenzoate (509 mg, 3.35 mmol) andK₂CO₃ (2.31 g, 16.75 mmol) and the reaction was stirred at 60° C. for 3hours, diluted with H₂O, and the resulting solution was extracted withEtOAc and washed with brine, dried over Na₂SO₄ and concentrated invacuo, followed by MPLC purification to yield Intermediate 7 as yellowoil (1.0 g, 99%).

¹H NMR (600 MHz, CD₃OD) δ 8.03 (d, J=2.35 Hz, 1H), 8.00 (dd, J=1.61,7.78 Hz, 1H), 7.62-7.70 (m, 1H), 7.54 (dd, J=2.64, 9.10 Hz, 1H), 7.39(td, J=1.17, 7.63 Hz, 1H), 7.20 (dd, J=0.88, 8.22 Hz, 1H), 6.84 (d,J=9.10 Hz, 1H), 3.74 (s, 3H).

EXAMPLE 17 Intermediate 8 Methyl2-((3-amino-5-chloropyridin-2-yl)oxy)benzoate

To a solution of Intermediate 7(1.0 g, 3.26 mmol) in MeOH (30 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (5.3 g, 81 mmol). Thesuspension was stirred at room temperature for 1 hour and was filtered,the filtrate was extracted with EtOAc (×2). The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The crudeIntermediate 8 (770 mg, 85%) was used in the next reaction withoutfurther purification.

¹H NMR (600 MHz, CD₃OD) δ 7.82 (dd, J=1.76, 7.92 Hz, 1H), 7.43-7.50 (m,1H), 7.12-7.18 (m, 1H), 6.90 (d, J=7.92 Hz, 1H), 6.85 (d, J=2.35 Hz,1H), 6.70 (d, J=8.51 Hz, 1H), 6.58 (dd, J=2.20, 8.66 Hz, 1H), 3.85 (s,3H).

EXAMPLE 18 Compound 10 Methyl2-{2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}benzoate

To Intermediate 8 (770 mg, 2.53 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (546 mg, 2.53 mmol) and the reaction wasstirred at room temperature for 16 hours. Solvent was removed in vacuoand the crude product was purified by flash column chromatography onsilica gel (0-30% EtOAc in hexanes) to yield Compound 10 (920 mg, 72%)as a yellow solid.

¹H NMR (600 MHz, CD₃OD) δ 7.79 (dd, J=2.35, 7.04 Hz, 1H), 7.65-7.69 (m,2H), 7.42-7.46 (m, 1H), 7.35-7.38 (m, 2H), 7.30-7.35 (m, 1H), 7.09 (dd,J=2.64, 8.80 Hz, 1H), 7.02-7.08 (m, 2H), 6.63 (d, J=8.51 Hz, 1H), 6.28(dd, J=1.61, 7.78 Hz, 1H), 3.74 (s, 3H).

EXAMPLE 19 Compound 112-{2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}benzoic acid

To Compound 10 (354 mg, 0.78 mmol) in MeOH (30 ml) was added NaOH (5M, 2ml) and stirred at room temperature for 3 hours. The mixture wasacidified with 10% HCl, extracted with EtOAc (×2). The combined organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was recrystallized from minimal MeOH and CH₂Cl₂to yield Compound 11 (278 mg, 81%).

¹H NMR (600 MHz, CD₃OD) δ 7.81 (d, J=7.34 Hz, 1H), 7.69 (d, J=2.05 Hz,1H), 7.65 (d, J=7.92 Hz, 1H), 7.40-7.45 (m, 1H), 7.29-7.37 (m, 3H), 7.11(dd, J=1.76, 8.51 Hz, 1H), 6.99 (t, J=7.63 Hz, 1H), 6.89-6.95 (m, 1H),6.72 (d, J=8.80 Hz, 1H), 6.18 (d, J=8.22 Hz, 1H).

EXAMPLE 20 Intermediate 9 (4-Chloro-2-nitrophenyl)(phenyl)sulfane

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (926 mg, 5.0 mmol) inMeOH (5 ml) was added benzenethiol (0.51 ml, 5.0 mmol) and 4M NaOH (1.25ml, 5.0 mmol) and the reaction was stirred at room temperature for 4hours, diluted with 1M NaOH, extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude product was purified by flash column chromatography on silica gel(0-5% EtOAc in hexanes) to yield Intermediate 9 as a yellow solid (1.31g, 98%).

1H NMR (CHLOROFORM-d) δ: 8.23 (d, J=2.3 Hz, 1H), 7.56-7.61 (m, 2H),7.48-7.53 (m, 3H), 7.30 (dd, J=8.8, 2.3 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H).

EXAMPLE 21 Intermediate 10 5-Chloro-2-(phenylthio)aniline

To a solution of Intermediate 9 (0.64 g, 2.4 mmol) in MeOH (20 ml) andTHF (20 ml) was added saturated aqueous NH₄Cl (20 ml) and zinc dust(3.95 g, 61 mmol). The suspension was stirred at room temperature for 3hours and was filtered; the filtrate was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo. The crude product was purified by flash column chromatographyon silica gel (5-10% EtOAc in hexanes) to yield Intermediate 10 as anoff-white solid (555 mg, 98%).

1H NMR (CHLOROFORM-d) δ: 7.38 (d, J=8.2 Hz, 1H), 7.24 (t, J=7.6 Hz, 2H),7.14 (t, J=7.3 Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 6.80 (d, J=2.3 Hz, 1H),6.74 (dd, J=8.2, 2.1 Hz, 1H), 4.42 (br. s., 2H).

EXAMPLE 22 Compound 12N-[5-Chloro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide

To Intermediate 10 (394 mg, 1.67 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (362 mg, 1.67 mmol) and the reaction wasstirred at room temperature for 72 hours, when additionalbenzofuran-2-sulfonyl chloride (362 mg, 1.67 mmol) and catalytic amountof DMAP was added. The reaction was heated at 100° C. for 6 hours andwas concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (0-5% EtOAc in hexanes) to yield Compound12 as an off-white solid (425 mg, 61%).

1H NMR (CHLOROFORM-d) δ: 8.03 (s, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.66 (dt,J=8.1, 0.9 Hz, 1H), 7.39-7.48 (m, 4H), 7.31-7.37 (m, 1H), 7.04-7.11 (m,4H), 6.89-6.93 (m, 2H).

EXAMPLE 23 Compound 13N-[5-Chloro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide

To a solution of Compound 12 (333 mg, 0.80 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (208 mg, ˜1.20 mmol) and the reaction was stirred at roomtemperature for 2 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (0-50% EtOAc in hexanes) toyield Compound 13 as a white solid (204 mg, 57%).

1H NMR (CHLOROFORM-d) δ: 9.70 (s, 1H), 7.79-7.94 (m, 4H), 7.69 (d, J=7.6Hz, 1H), 7.34-7.57 (m, 7H), 7.17 (d, J=7.9 Hz, 1H).

EXAMPLE 24 Compound 14N-[5-Chloro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide

To a solution of Compound 12 (333 mg, 0.80 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (208 mg, ˜1.20 mmol) and the reaction was stirred at roomtemperature for 2 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (0-50% EtOAc in hexanes) toyield Compound 14 as a white solid (129 mg, 37%).

1H NMR (CHLOROFORM-d) δ: 10.66 (s, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.63(dt, J=7.9, 1.0 Hz, 1H), 7.30-7.52 (m, 10H), 7.12 (dd, J=8.2, 2.1 Hz,1H).

EXAMPLE 25 Intermediate 11 2-Amino-4-chloro-N-phenylbenzamide

A mixture of 4-chloro-isatoic anhydride (594 mg, 3.0 mmol), aniline (275μl, 3.0 mmol), and NaOH (12 mg, 0.3 mmol) in dioxane (5 ml) was refluxedat 110° C. for 2 hours. The mixture was cooled to room temperature andwas filtered. The filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (25% EtOAc inhexanes) to yield Intermediate 11 (200 mg, 27%).

1H NMR (CHLOROFORM-d) δ: 7.70 (br. s., 1H), 7.55 (dd, J=8.6, 1.0 Hz,2H), 7.33-7.43 (m, 3H), 7.13-7.21 (m, 1H), 6.64-6.74 (m, 2H), 5.62 (br.s., 2H).

EXAMPLE 26 Compound 152-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chloro-N-phenylbenzamide

To Intermediate 11 (200 mg, 0.81 mmol) in pyridine (2 ml) was addedbenzofuran-2-sulfonyl chloride (176 mg, 0.81 mmol) and a catalyticamount of DMAP. The reaction was stirred at room temperature for 6hours, when additional benzofuran-2-sulfonyl chloride (88 mg, 0.41 mmol)was added. The reaction was continued for a total of 120 hours and wasconcentrated in vacuo. The crude reaction mixture was acidified with 6MHCl, extracted with EtOAc (×3). The combined organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (25% EtOAc inhexanes) to yield Compound 15 as an off-white solid (135 mg, 39%).

1H NMR (CHLOROFORM-d) δ: 11.06 (s, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.76 (s,1H), 7.61 (dt, J=7.7, 1.1 Hz, 1H), 7.43-7.51 (m, 3H), 7.15-7.43 (m, 7H),7.11 (dd, J=8.5, 2.1 Hz, 1H).

EXAMPLE 27 Compound 16N-(5-Chloro-2-cyanophenyl)-1-benzofuran-2-sulfonamide

To 2-amino-4-chlorobenzonitrile (552 mg, 3.62 mmol) in pyridine (5 ml)was added benzofuran-2-sulfonyl chloride (781 mg, 3.62 mmol) and thereaction was stirred at 100° C. for 16 hours, then additionalbenzofuran-2-sulfonyl chloride (842 mg, 3.90 mmol) was added. Thereaction was continued for 24 hours and was concentrated in vacuo. Thecrude product was purified by flash column chromatography on silica gel(0-100% EtOAc in hexanes) to yield Compound 16 (550 mg, 36%).

¹H NMR (600 MHz, CD₃OD) δ 7.72 (dt, J=1.03, 7.92 Hz, 1H), 7.64 (d,J=8.51 Hz, 1H), 7.57-7.60 (m, 1H), 7.53 (d, J=2.05 Hz, 1H), 7.49-7.52(m, 1H), 7.41-7.42 (m, 1H), 7.34-7.39 (m, 2H).

EXAMPLE 28 Compound 17N-[5-Chloro-2-(phenylacetyl)phenyl]-1-benzofuran-2-sulfonamide

To a solution of Compound 16 (128 mg, 0.39 mmol) in THF (2 ml) was addedbenzylmagnesium chloride (0.6 ml, 1.16 mmol, 2M in THF) at 0° C. Afterit was stirred at room temperature for 2 hours, the reaction wasquenched with water, extracted with EtOAc (×2), washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The crude product was purified byflash column chromatography on silica gel (0-30% EtOAc in hexanes) toyield Compound 17 (91 mg, 55%).

¹H NMR (600 MHz, CDCL₃) δ 11.95 (s, 1H), 7.82-7.91 (m, 2H), 7.66 (d,J=7.92 Hz, 1H), 7.47-7.50 (m, 2H), 7.42-7.46 (m, 1H), 7.32 (td, J=1.03,7.41 Hz, 1H), 7.23-7.30 (m, 3H), 7.14 (d, J=7.04 Hz, 2H), 7.05 (dd,J=2.05, 8.51 Hz, 1H), 4.23 (s, 2H).

EXAMPLE 29 Compound 18N-{5-Chloro-2-[(1Z)-N-methoxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide

A mixture of Compound 17 (91 mg, 0.214 mmol), O-methylhydroxylaminehydrochloride (177 mg, 2.14 mmol) and TEA (0.8 ml) in THF (2 ml) washeated at 80° C. overnight. The reaction mixture was cooled down to roomtemperature, diluted with EtOAc, filtered, and the filtrate wasconcentrated in vacuo. The crude residue was purified by flash columnchromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound18 (56 mg, 58%).

¹H NMR (600 MHz, CDCL₃) δ 11.70 (s, 1H), 7.75 (d, J=2.05 Hz, 1H),7.63-7.67 (m, 1H), 7.49-7.53 (m, 1H), 7.43-7.48 (td, J=1.32, 7.85Hz,1H), 7.40 (d, J=0.88 Hz, 1H), 7.33 (td, J=1.17, 7.48 Hz, 1H), 7.22 (d,J=8.80 Hz, 1H), 7.09-7.15 (m, 3H), 6.97-7.02 (m, 2H), 6.93 (dd, J=2.20,8.66 Hz, 1H), 4.18 (s, 3H), 4.01 (s, 2H).

EXAMPLE 30 Compound 19N-{5-Chloro-2-[(1Z)-N-hydroxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide

The mixture of Compound 17 (121 mg, 0.28 mmol), hydroxylaminehydrochloride (198 mg, 2.80 mmol) and TEA (0.8 ml) in THF (2 ml) washeated at 80° C. overnight. The reaction mixture was cooled down to roomtemperature, diluted with EtOAc, filtered away salt and filtrate wasconcentrated in vacuo. The crude residue was purified by flash columnchromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound19 (100 mg, 80%).

¹H NMR (600 MHz, CDCl₃) δ 11.40 (br. s., 1H), 7.76 (d, J=2.05 Hz, 1H),7.66 (dt, J=1.03, 7.92 Hz, 1H), 7.50-7.53 (m, 1H), 7.45-7.48 (m, 1H),7.43 (d, J=0.88 Hz, 1H), 7.30-7.36 (m, 1H), 7.23-7.28 (m, 1H), 7.12-7.17(m, 3H), 7.02-7.09 (m, 2H), 6.95 (dd, J=2.05, 8.51 Hz, 1H), 4.08 (s,2H).

EXAMPLE 31 Intermediate 12 1-(Benzyloxy)-4-chloro-2-nitrobenzene

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (409 mg, 2.33 mmol) inDMF (10 ml) was added phenylmethanol (0.24 ml, 2.33 mmol) and K₂CO₃ (1.6g, 11.65 mmol) and the reaction was stirred at 60° C. for 16 hours. Thereaction was diluted with H₂O, and the resulting solution was extractedwith EtOAc and washed with brine, dried over Na₂SO₄ and concentrated invacuo, followed by MPLC purification to yield Intermediate 12 as yellowsolid (607 mg, 99%).

¹H NMR (600 MHz, CD₃OD) δ 7.86 (d, J=2.64 Hz, 1H), 7.57 (dd, J=2.79,8.95 Hz, 1H), 7.43-7.47 (m, 2H), 7.36-7.40 (m, 2H), 7.30-7.35 (m, 2H),5.27 (s, 2H).

EXAMPLE 32 Intermediate 13 2-(Benzyloxy)-5-chloroaniline

To a solution Intermediate 12 (605 mg, 2.30 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (3.7 g, 57 mmol). Thesuspension was stirred at room temperature for 1 hour, was filtered, andthe filtrate was extracted with EtOAc (×2). The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The crudeIntermediate 13 (475 mg, 89%) was used in the next reaction withoutfurther purification.

¹H NMR (600 MHz, CD₃OD) δ 7.42-7.49 (m, 2H), 7.34-7.40 (m, 2H),7.26-7.33 (m, 1H), 6.80 (d, J=8.80 Hz, 1H), 6.73 (d, J=2.64 Hz, 1H),6.56 (dd, J=2.49, 8.66 Hz, 1H), 5.07 (s, 2H).

EXAMPLE 33 Compound 20N-[2-(Benzyloxy)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

To Intermediate 13 (233 mg, 1.0 mmol) in pyridine (3 ml) was addedbenzofuran-2-sulfonyl chloride (216 mg, 1.0 mmol) and the reaction wasstirred at 100° C. for 16 hours. The solvent was removed in vacuo andthe crude product was purified by flash column chromatography on silicagel (0-30% EtOAc in hexanes) to yield the Compound 20 (304 mg, 74%) as ayellow solid.

¹H NMR (600 MHz, acetone) δ 7.76 (dt, J=1.03, 7.92 Hz, 1H), 7.56 (d,J=2.64 Hz, 1H), 7.47-7.53 (m, 2H), 7.45 (d, J=0.59 Hz, 1H), 7.35-7.40(m, 1H), 7.24-7.31 (m, 3H), 7.20-7.24 (m, 2H), 7.14 (dd, J=2.64, 8.80Hz, 1H), 7.00 (d, J=9.10 Hz, 1H), 4.95 (s, 2H).

EXAMPLE 34 Intermediate 14 5-Chloro-2-(phenylethynyl)aniline

To 5-chloro-2-iodoaniline (1.27 g, 5.0 mmol) and ethynylbenzene (0.60ml, 5.5 mmol) in Et₃N (10 ml) was added CuI (5.0 mg, 0.025 mmol) andPd(PPh₃)₂Cl₂ (18 mg, 0.025 mmol) and the mixture was stirred at roomtemperature for 16 hours, diluted with EtOAc and was filtered through apad of Celite. The filtrate was concentrated and the residue waspurified by flash column chromatography on silica gel (0-10% EtOAc inhexanes) to yield Intermediate 14 as beige solid (1.12 g, 98%).

1H NMR (CHLOROFORM-d) δ: 7.46-7.56 (m, 2H), 7.32-7.39 (m, 3H), 7.28 (d,J=8.2 Hz, 1H), 6.66-6.75 (m, 2H), 4.37 (br. s., 2H).

EXAMPLE 35 Compound 21N-[5-Chloro-2-(phenylethynyl)phenyl]-1-benzofuran-2-sulfonamide

To Intermediate 14 (506 mg, 2.22 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (482 mg, 2.22 mmol) and a catalyticamount of DMAP. The reaction was stirred at room temperature for 4hours, when additional benzofuran-2-sulfonyl chloride (121 mg, 0.56mmol) was added. The reaction was continued for 16 hours and wasconcentrated in vacuo. The crude reaction mixture was acidified with 1MHCl, extracted with EtOAc (×3). The combined organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (0-5% EtOAc inhexanes) to yield Compound 21 as a white solid (516 mg, 57%).

1H NMR (CHLOROFORM-d) δ: 7.71 (d, J=2.1 Hz, 1H), 7.62-7.65 (m, 1H),7.51-7.54 (m, 2H), 7.49 (s, 1H), 7.38-7.44 (m, 5H), 7.32-7.35 (m, 2H),7.29-7.32 (m, 1H), 7.10 (dd, J=8.2, 2.1 Hz, 1H).

EXAMPLE 36 Compound 22N-[5-Chloro-2-(2-phenylethyl)phenyl]-1-benzofuran-2-sulfonamide

A mixture of Compound 21 (110 mg, 0.27 mmol) and 10% palladium onactivated carbon (29 mg, 0.027 mmol) in EtOAc (5 ml) was stirred at roomtemperature under excess hydrogen gas in a balloon for 4 hours. Themixture was filtered and the filtrate was concentrated to yield Compound22 as off-white solid (103 mg, 93%).

1H NMR (CHLOROFORM-d) δ: 7.60-7.63 (m, 1H), 7.46-7.50 (m, 1H), 7.42-7.46(m, 1H), 7.30-7.35 (m, 2H), 7.28 (d, J=0.9 Hz, 1H), 7.18-7.27 (m, 3H),7.10 (dd, J=8.2, 2.3 Hz, 1H), 6.98-7.03 (m, 3H), 6.34 (s, 1H), 2.72-2.79(m, 4H).

EXAMPLE 37 Compound 23N-{5-Chloro-2-[((Z)-2-phenylethenyl]phenyl}-1-benzofuran-2-sulfonamide

A mixture of Compound 21 (140 mg, 0.34 mmol) and 5% Lindlar's catalyst(Aldrich Lot#BCBG1137V, 144 mg, 0.068 mmol) in EtOAc (5 ml) was stirredat room temperature under excess hydrogen gas in a balloon for 4 hours.The mixture was then place under 50 psi hydrogen gas using a Parrapparatus for 3 h, and was filtered. The filtrate was concentrated andthe crude product was purified by flash column chromatography on silicagel (5-10% EtOAc in hexanes) to yield Compound 23 (75 mg, 53%).

1H NMR (CHLOROFORM-d) δ: 7.61-7.66 (m, 2H), 7.42-7.48 (m, 2H), 7.30-7.36(m, 2H), 7.11-7.16 (m, 1H), 7.06-7.11 (m, 2H), 7.01-7.06 (m, 2H),6.94-6.98 (m, 2H), 6.87 (s, 1H), 6.72 (d, J=12.0 Hz, 1H), 6.25 (d,J=12.0 Hz, 1H).

EXAMPLE 38 Intermediate 15 (4-Methyl-2-nitrophenyl)(phenyl)sulfane

To a solution of 1-bromo-4-methyl-2-nitrobenzene (1.32 g, 6.11 mmol) inMeOH (10 ml) was added benzenethiol (0.8 ML, 6.11 mmol) and NaOH (1.5ml, 5M) and the reaction was stirred at room temperature for 16 hours,diluted with H₂O, and the resulting solution was extracted with EtOAcand washed with brine, dried over Na₂SO₄ and concentrated in vacuo,followed by MPLC purification to yield Intermediate 15 (1.0 g, 67%).

¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=1.17 Hz, 1H), 7.53-7.59 (m, 2H),7.43-7.49 (m, 3H), 7.15 (dd, J=2.05, 8.50 Hz, 1H), 6.77 (d, J=8.20 Hz,1H), 2.36 (s, 3H).

EXAMPLE 39 Intermediate 16 5-Methyl-2-(phenylthio)aniline

To a solution Intermediate 15 (1.0 g, 4.76 mmol) in MeOH (50 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (5.3 g, 82 mmol). Thesuspension was stirred at room temperature for 1 hour, and was filtered,and the filtrate was extracted with EtOAc (×2). The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 16 (760 mg, 87%) was used in the next reactionwithout further purification.

¹H NMR (300 MHz, CD₃OD) δ 7.13-7.26 (m, 3H), 6.98-7.11 (m, 3H), 6.68 (d,J=0.59 Hz, 1H), 6.44-6.58 (m, 1H), 2.26 (s, 3H).

EXAMPLE 40 Compound 24N-[5-Methyl-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide

To Intermediate 16 (335 mg, 1.56 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (335 mg, 1.56 mmol) and the reaction wasstirred at 100° C. for 4 hours, then additional benzofuran-2-sulfonylchloride (168 mg, 0.78 mmol) was added and the reaction was stirred at100° C. for 16 hours. 2M NaOH (2 ml) was added to the mixture, and itwas heated to 100° C. for 1 hour. The mixture was diluted with water,and the products extracted with EtOAc (×2). The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Compound 24 (311 mg, 51%).

¹H NMR (300 MHz, CDCl₃) δ 7.99 (s, 1H), 7.57-7.67 (m, J=11.72 Hz, 2H),7.24-7.47 (m, 4H), 6.99-7.07 (m, 3H), 6.83-6.96 (m, 3H), 2.39 (s, 3H).

EXAMPLE 41 Compound 25N-[5-Methyl-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide

To a solution of Compound 24 (122 mg, 0.31 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (62 mg, 0.31 mmol) and the reaction was stirred at 0° C. for30 min and was concentrated. The residue was purified by flash columnchromatography on silica gel (100% EtOAc) to yield Compound 25 (98 mg,77%).

¹H NMR (300 MHz, CDCl₃) δ 10.48 (br. s., 1H), 7.60 (d, J=7.91 Hz, OH),7.55 (s, 1H), 7.50 (d, J=1.76 Hz, 1H), 7.48 (d, J=1.47 Hz, 1H),7.38-7.44 (m, 2H), 7.23-7.37 (m, 6H), 6.95 (dd, J=0.88, 7.91 Hz, 1H),2.35 (s, 3H).

EXAMPLE 42 Compound 26N-[5-Methyl-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide

To a solution of Compound 24 (118 mg, 0.30 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (150 mg, 0.75 mmol) and the reaction was stirred at roomtemperature for 2 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 26 (117 mg, 92%).

¹H NMR (300 MHz, CDCl₃) δ 7.76-7.88 (m, 3H), 7.67 (d, J=7.91 Hz, 1H),7.58 (s, 1H), 7.26-7.53 (m, 7H), 7.02 (d, J=8.21 Hz, 1H), 2.37 (s, 3H).

EXAMPLE 43 Intermediate 17 (4-Fluoro-2-nitrophenyl)(phenyl)sulfane

To a solution of 1-chloro-4-fluoro-2-nitrobenzene (1.20 g, 6.82 mmol) inMeOH (10 ml) was added benzenethiol (1.0 ML, 10.22 mmol) and NaOH (1.5ml, 5M) and the reaction was stirred at room temperature for 16 hours,diluted with H₂O, and the resulting solution was extracted with EtOAcand washed with brine, dried over Na₂SO₄ and concentrated in vacuo,followed by MPLC purification to yield Intermediate 17 (1.3 g, 80%).

¹H NMR (300 MHz, CDCl₃) δ 7.94 (dd, J=2.78, 8.35 Hz, 1H), 7.54-7.63 (m,2H), 7.44-7.52 (m, 3H), 7.03-7.18 (m, 1H), 6.86 (dd, J=4.98, 9.08 Hz,1H).

EXAMPLE 44 Intermediate 18 5-Fluoro-2-(phenylthio)aniline

To a solution Intermediate 17 (1.3 g, 5.20 mmol) in MeOH (50 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (8.4 g, 130 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 18 (980 mg, 86%) was used in the next reactionwithout further purification.

¹H NMR (300 MHz, CDCl₃) δ 7.35-7.50 (m, 1H), 7.18-7.30 (m, 2H),7.00-7.17 (m, 3H), 6.37-6.57 (m, 2H), 4.02 (br. s., 2H).

EXAMPLE 45 Compound 27N-[5-Fluoro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide

To Intermediate 18 (980 mg, 4.45 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (962 mg, 4.45 mmol) and the reaction wasstirred at 100° C. for 16 hours and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Compound 27 (679 mg, 38%).

¹H NMR (300 MHz, CDCl₃) δ 8.14 (br. s, 1H), 7.56-7.67 (m, 2H), 7.29-7.54(m, 5H), 7.00-7.08 (m, 3H), 6.78-6.90 (m, 3H).

EXAMPLE 46 Compound 28N-[5-Fluoro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide

To a solution of Compound 27 (485 mg, 0.71 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (143 mg, 0.71 mmol) and the reaction was stirred at 0° C.for 30 min, and the solution was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 28 (420 mg, 83%).

¹H NMR (300 MHz, CDCl) δ 10.73 (br. s., 1H), 7.63 (d, J=7.91 Hz, 1H),7.39-7.56 (m, 6H), 7.28-7.38 (m, 5H), 6.84 (td, J=2.34, 8.06 Hz, 1H).

EXAMPLE 47 Compound 29N-[5-Fluoro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide

To a solution of Compound 27 (220 mg, 0.55 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (276 mg, 1.38 mmol) and the reaction was stirred at roomtemperature for 2 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 29 (170 mg, 72%).

¹H NMR (300 MHz, CDCl₃) δ 7.97 (dd, J=6.01, 8.94 Hz, 1H), 7.78-7.89 (m,2H), 7.68 (d, J=7.62 Hz, 1H), 7.29-7.61 (m, 8H), 6.78-6.97 (m, 1H).

EXAMPLE 48 Intermediate 19 Methyl2-((4-Chloro-2-nitrophenoxy)methyl)benzoate

To a solution of 4-chloro-2-nitrophenol (541 mg, 3.12 mmol) in DMF (10ml) was added methyl 2-(bromomethyl)benzoate (714 mg, 3.12 mmol) andK₂CO₃ (1.3 g, 9.35 mmol). The reaction was stirred at room temperaturefor 16 hours, diluted with H₂O, and the resulting solution was extractedwith EtOAc and washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by MPLC to yield Intermediate 19(959 mg,96%).

¹H NMR (600 MHz, CDCl₃) δ 8.08 (dd, J=1.32, 7.78 Hz, 1H), 7.92 (d,J=2.64 Hz, 1H), 7.91 (d, J=7.92 Hz, 1H), 7.59-7.68 (m, 1H), 7.48-7.54(m, 1H), 7.43 (t, J=7.63 Hz, 1H), 7.20 (d, J=9.10 Hz, 1H), 5.66 (s, 2H),3.88-3.99 (m, 3H).

EXAMPLE 49 Intermediate 20 Methyl2-((2-(Benzofuran-2-sulfonamido)-4-chlorophenoxy)methyl)benzoate

To a solution Intermediate 19 (959 mg, 2.99 mmol) in MeOH (50 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (3.9 g, 60 mmol). Thesuspension was stirred at room temperature for 1 hour, filtered, and thefiltrate was extracted with EtOAc (×2). The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The crudeIntermediate 20 (713 mg, 82%) was used in the next reaction withoutfurther purification.

¹H NMR (600 MHz, CDCl₃) δ 8.01 (dd, J=1.32, 7.78 Hz, 1H), 7.61-7.66 (m,1H), 7.55 (td, J=1.47, 7.63 Hz, 1H), 7.36-7.42 (m, 1H), 6.69-6.74 (m,2H), 6.59-6.64 (m, 1H), 5.48 (s, 2H), 3.94 (br. s., 2H), 3.89 (s, 3H).

EXAMPLE 50 Compound 30 Methyl2-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoate

To Intermediate 20 (329 mg, 1.13 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (244 mg, 1.13 mmol) and the reaction wasstirred at 100° C. for 16 hours and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Compound 30 (231 mg, 43%).

¹H NMR (600 MHz, CDCl₃) δ 7.99-8.07 (m, 1H), 7.58-7.67 (m, 2H), 7.51(br. s., 1H), 7.33-7.44 (m, 4H), 7.22-7.33 (m, 3H), 6.89-7.05 (m, 1H),6.71 (dd, J=4.70, 8.80 Hz, 1H), 5.35 (d, J=4.40 Hz, 2H), 3.89 (d, J=4.70Hz, 3H).

EXAMPLE 51 Compound 312-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoicAcid

To Compound 30 (180 mg, 0.38 mmol) in MeOH (30 ml) was added 5M NaOH (2ml) and stirred at room temperature for 16 hours. The mixture wasacidified with 10% HCl, extracted with EtOAc (×2). The combined organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was recrystallized from minimal MeOH and CH₂Cl₂to yield Compound 31(168 mg, 96%).

¹H NMR (600 MHz, CDCl₃) δ 8.06 (dd, J=1.32, 7.78 Hz, 1H), 7.58-7.64 (m,2H), 7.23-7.43 (m, 7H), 7.00 (dd, J=2.64, 8.80 Hz, 1H), 6.72 (d, J=8.80Hz, 1H), 5.32 (s, 2H).

EXAMPLE 52 Intermediate 21 Methyl2-((4-Chloro-2-nitrophenyl)thio)benzoate

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (1.1 g, 6.0 mmol) inMeOH (10 ml) was added methyl 2-mercaptobenzoate (1.0 g, 6.0 mmol) and4M NaOH (1.5 ml, 6.0 mmol) and the reaction was stirred at roomtemperature for 2 hours, diluted with H₂O, and the resulting suspensionwas filtered and washed with H₂O to yield Intermediate 21 as a yellowsolid (2.0 g, crude). The crude product was used in the next reactionwithout further purification.

EXAMPLE 53 Intermediate 22 Methyl2-((2-amino-4-chlorophenyl)thio)benzoate hydrochloride salt

To a solution of Intermediate 21 (0.99 g, 3.1 mmol) in MeOH (15 ml) andCH₂Cl₂ (15 ml) was added saturated aqueous NH₄Cl (20 ml) and zinc dust(5.0 g, 77 mmol). The suspension was stirred at room temperature for 30minutes and was filtered, the filtrate was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo. The crude product was dissolved in Et₂O, and 2M HCl in Et₂O (4ml) was added. The resulting suspension was filtered and the solid waswashed with Et₂O (×3) to yield Intermediate 22 as a white solid (0.75 g,75%).

1H NMR (METHANOL-d4) δ: 8.01 (d, J=7.6 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H),7.31-7.41 (m, 1H), 7.20-7.28 (m, 2H), 7.15 (dd, J=8.5, 1.8 Hz, 1H), 6.78(d, J=7.9 Hz, 1H), 3.93 (s, 3H).

EXAMPLE 54 Compound 322-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicAcid

To Intermediate 22 (0.75 g, 2.27 mmol) in pyridine (4 ml) was addedbenzofuran-2-sulfonyl chloride (493 mg, 2.27 mmol) and the reaction wasstirred at room temperature for 16 hours, when additionalbenzofuran-2-sulfonyl chloride (250 mg, 1.15 mmol) was added. Thereaction was continued for 24 hours and was concentrated in vacuo. Theresidue was dissolved in MeOH and was treated with 4M NaOH (3 ml) at100° C. for 15 minutes, and cooled, and acidified with 6M HCl, and theproducts were extracted with EtOAc (×2). The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo.The crude product was triturated with 10% MeOH in CH₂Cl₂ to yieldCompound 32 as a pinkish white solid (0.75 g, 66%).

1H NMR (acetone) δ: 11.56 (br. s., 1H), 9.21 (s, 1H), 7.99 (dd, J=7.8,1.6 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.74 (dt, J=7.9, 1.0 Hz, 1H), 7.57(d, J=3.8 Hz, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.51 (ddd, J=8.4, 7.1, 1.2Hz, 1H), 7.45 (dd, J=8.2, 0.9 Hz, 1H), 7.37 (ddd, J=7.9, 7.0, 0.9 Hz,1H), 7.33 (dd, J=8.2, 2.3 Hz, 1H), 7.11 (td, J=7.5, 1.2 Hz, 1H),6.95-7.00 (m, 1H), 6.41 (dd, J=8.1, 1.0 Hz, 1H).

EXAMPLE 55 Intermediate 23 Methyl3-((4-Chloro-2-nitrophenyl)thio)benzoate

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (1.0 g, 5.6 mmol) inMeOH (10 ml) was added methyl 3-mercaptobenzoate (0.95 g, 5.6 mmol) and4M NaOH (1.4 ml, 5.6 mmol) and the reaction was stirred at roomtemperature for 2 hours, diluted with H₂O, and the resulting suspensionwas filtered and washed with H₂O to yield Intermediate 23 as a yellowsolid (1.9 g, 100%).

1H NMR (CHLOROFORM-d) δ: 8.21-8.26 (m, 2H), 8.15-8.20 (m, 1H), 7.73-7.78(m, 1H), 7.56-7.61 (m, 1H), 7.31 (dt, J=8.8, 2.1 Hz, 1H), 6.77 (dd,J=8.8, 1.8 Hz, 1H), 3.94 (s, 3H).

EXAMPLE 56 Intermediate 24 Methyl 3-((2-Amino4-chlorophenyl)thio)benzoate

To a solution of Intermediate 23 (0.83 g, 2.6 mmol) in MeOH (15 ml) andCH₂Cl₂ (15 ml) was added saturated aqueous NH₄Cl (20 ml) and zinc dust(4.2 g, 64 mmol). The suspension was stirred at room temperature for 1hour and was filtered, and the filtrate was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo. The crude product Intermediate 24 (0.77 g, 100%) was used inthe next reaction without further purification.

1H NMR (CHLOROFORM-d) δ: 7.77-7.82 (m, 2H), 7.38 (d, J=8.2 Hz, 1H),7.27-7.32 (m, 1H), 7.19 (ddd, J=7.9, 2.1, 1.2 Hz, 1H), 6.80 (d, J=2.3Hz, 1H), 6.74 (dd, J=8.2, 2.1 Hz, 1H), 3.89 (s, 3H).

EXAMPLE 57 Compound 333-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicAcid

To Intermediate 24 (0.76 g, 2.6 mmol) in pyridine (4 ml) was addedbenzofuran-2-sulfonyl chloride (0.56 g, 2.6 mmol) and the reaction wasstirred at room temperature for 16 hours, when additionalbenzofuran-2-sulfonyl chloride (0.28 g, 1.3 mmol) was added. Thereaction was continued for 24 hours and was concentrated in vacuo. Theresidue was taken up in MeOH and was treated with 4M NaOH (3 ml) at 100°C. for 15 minutes, and cooled, and acidified with 6M HCl, and extractedwith EtOAc (×2). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The crude product waspurified by flash column chromatography on silica gel (0-50% EtOAc inhexanes) to yield Compound 33 (0.75 g, 63%).

1H NMR (acetone) δ: 7.79 (dt, J=8.0, 1.3 Hz, 1H), 7.73 (dt, J=7.9, 1.0Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.69 (t, J=1.6 Hz, 1H), 7.46-7.53 (m,3H), 7.32-7.37 (m, 2H), 7.24-7.30 (m, 2H), 7.17 (ddd, J=7.9, 2.1, 1.2Hz, 1H).

EXAMPLE 58 Intermediate 25 Methyl4-((4-Chloro-2-nitrophenyl)thio)benzoate

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (1.0 g, 5.6 mmol) inMeOH (10 ml) was added methyl 4-mercaptobenzoate (0.95 g, 5.6 mmol) and4M NaOH (1.4 ml, 5.6 mmol) and the reaction was stirred at roomtemperature for 2 hours, diluted with H₂O, and the resulting suspensionwas filtered and washed with H₂O to yield Intermediate 25 As a yellowsolid (1.4 g, 78%).

1H NMR (CHLOROFORM-d) δ: 8.22 (s, 1H), 8.12 (d, J=7.9 Hz, 2H), 7.63 (d,J=8.2 Hz, 2H), 7.34 (dd, J=8.8, 2.3 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H),3.97 (s, 3H).

EXAMPLE 59 Intermediate 26 Methyl4-((2-Amino-4-chlorophenyl)thio)benzoate

To a solution of Intermediate 25 (0.69 g, 2.1 mmol) in MeOH (15 ml) andCH₂Cl₂ (15 ml) was added saturated aqueous NH₄Cl (20 ml) and zinc dust(3.5 g, 54 mmol). The suspension was stirred at room temperature for 1hour and was filtered, and the filtrate was extracted with EtOAc (×2).The organic layer was washed with brine, and dried over Na₂SO₄, andconcentrated in vacuo. The crude product Intermediate 26 (0.63 g, 99%)was used in the next reaction without further purification.

1H NMR (CHLOROFORM-d) δ: 7.87 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.2 Hz, 1H),7.06 (d, J=8.5 Hz, 2H), 6.82 (d, J=2.3 Hz, 1H), 6.75 (dd, J=8.2, 2.3 Hz,1H), 4.36 (br. s., 2H), 3.88 (s, 3H).

EXAMPLE 60 Compound 344-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicAcid

To Intermediate 26 (0.62 g, 2.1 mmol) in pyridine (4 ml) was addedbenzofuran-2-sulfonyl chloride (0.46 g, 2.1 mmol) and the reaction wasstirred at room temperature for 16 hours, when additionalbenzofuran-2-sulfonyl chloride (0.23 g, 1.1 mmol) was added. Thereaction was continued for 24 hours and was concentrated in vacuo. Theresidue was taken up in MeOH and was treated with 4M NaOH (3 ml) at 100°C. for 15 minutes, and cooled, and acidified with 6M HCl, and theproducts extracted with EtOAc (×2). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude product was purified by flash column chromatography on silica gel(0-50% EtOAc in hexanes) followed by re-crystallization from minimalacetone and CH₂Cl₂ to yield Compound 34 (0.23 g, 24%).

1H NMR (acetone) δ: 11.17 (br. s., 1H), 9.23 (br. s., 1H), 7.78 (d,J=2.1 Hz, 1H), 7.69-7.75 (m, 3H), 7.54 (s, 1H), 7.45-7.51 (m, 3H),7.32-7.36 (m, 2H), 6.95-6.98 (m, 2H).

EXAMPLE 61 Intermediate 27 Methyl 3-((4-Chloro-2-nitrophenoxy)methyl)benzoate

To a solution of 4-chloro-2-nitrophenol (611 mg, 3.52 mmol) in DMF (10ml) was added methyl 3-(bromomethyl)benzoate (807 mg, 3.52 mmol) andK₂CO₃ (1.46 g, 10.57 mmol) and the reaction was stirred at roomtemperature for 16 hours, and diluted with H₂O, and the resultingsolution was extracted with EtOAc and washed with brine, and dried overNa₂SO₄ and concentrated in vacuo, followed by MPLC purification to yieldIntermediate 27 (959 mg, 96%).

¹H NMR (600 MHz, CDCl₃) δ 8.08 (s, 1H), 8.02 (d, J=7.92 Hz, 1H), 7.87(d, J=2.64 Hz, 1H), 7.69 (d, J=7.63 Hz, 1H), 7.46-7.51 (m, 2H), 7.06 (d,J=8.80 Hz, 1H), 5.26 (s, 2H), 3.94 (s, 3H).

EXAMPLE 62 Intermediate 28 Methyl3-((2-(Benzofuran-2-sulfonamido)-4-chlorophenoxy)methyl)benzoate

To a solution Intermediate 27 (630 mg, 1.96 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (2.6 g, 39 mmol). Thesuspension was stirred at room temperature for 1 hour and was filtered,and the filtrate was extracted with EtOAc (×2). The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 28 (561 mg, 98%) was used in the next reactionwithout further purification.

¹H NMR (600 MHz, CDCl₃) δ 8.09 (dt, J=0.88, 1.76 Hz, 1H), 8.01 (d,J=7.34 Hz, 1H), 7.61 (d, J=7.63 Hz, 1H), 7.47 (t, J=7.78 Hz, 1H),6.69-6.73 (m, 2H), 6.63 (dd, J=2.64, 8.51 Hz, 1H), 5.09 (s, 2H), 3.93(s, 3H).

EXAMPLE 63 Compound 35 Methyl3-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4chlorophenoxy}methyl)benzoate

To Intermediate 28 (561 mg, 1.93 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (416 mg, 1.93 mmol) and the reaction wasstirred at 100° C. for 16 hours and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Compound 35 (651 mg, 72%).

¹H NMR (600 MHz, CDCl₃) δ 8.00-8.06 (m, 1H), 7.97 (d, J=0.88 Hz, 1H),7.60-7.67 (m, 2H), 7.42-7.49 (m, 2H), 7.36-7.40 (m, 2H), 7.28-7.35 (m,2H), 6.99 (dd, J=2.49, 8.66 Hz, 1H), 6.72 (d, J=8.80 Hz, 1H), 4.95 (s,2H), 3.95 (s, 3H).

EXAMPLE 64 Compound 363-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoicAcid

To Compound 35 (506 mg, 1.07 mmol) in MeOH (30 ml) was added 5M NaOH (2ml) and the solution stirred at room temperature for 16 hours. Themixture was acidified with 10% HCl, and extracted with EtOAc (×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was recrystallized from minimalMeOH and CH₂Cl₂ to yield Compound 36 (484 mg, 98%).

¹H NMR (600 MHz, DMSO-d₆) δ 13.01 (br. s., 1H), 10.57 (s, 1H), 7.78-7.84(m, 2H), 7.62-7.67 (m, 1H), 7.42-7.47 (m, 2H), 7.37-7.42 (m, 2H),7.31-7.35 (m, 1H), 7.27-7.31 (m, 2H), 7.24 (dd, J=2.35, 8.80 Hz, 1H),7.00 (d, J=8.80 Hz, 1H), 4.87 (s, 2H).

EXAMPLE 65 Intermediate 29 Isochroman-1-one

To isochroman (3 g, 22.4 mmol) in xylene (30 ml) was added SeO₂ (2.48 g,22.4 mmol) and the mixture stirred at 140° C. for 20 hours, and thenadditional SeO₂ (2.48 g, 22.4 mmol) was added and the reaction heatedfor 24 hours. The mixture was cooled down to room temperature, SeO₂ wasfiltered away and xylene was removed in vacuo. The crude residue waspurified by flash column chromatography on silica gel (0-20% EtOAc inhexanes) to yield Intermediate 29 (2.69g, 81%) as a pale red liquid.

¹H NMR (600 MHz, CDCl₃) δ 8.10 (dd, J=0.88, 7.63 Hz, 1H), 7.54 (td,J=1.47, 7.48 Hz, 1H), 7.37-7.41 (m, 1H), 7.24-7.28 (m, 1H), 4.51-4.55(m, 2H), 3.06 (t, J=6.02 Hz, 2H).

EXAMPLE 66 Intermediate 30 2-(2-Hydroxyethyl)benzoic Acid

To a solution of Intermediate 29 (2.69 g, 17.97 mmol) in Et₂O anhydrous(50 ml) was added powdered KOH (2.01 g, 35.94 mmol), and the reactionwas stirred at room temperature for 12 hours. The ether solution wasdecanted, the residue solid was washed with ether, then dissolved inwater. The aqueous solution was acidified with 10% HCl and thenextracted with ether (×3). The combine ether layers was dried overNa₂SO₄ and concentrated in vacuo to yield crude Intermediate 30 (˜2 g)which was used quickly in the next step without purification.

¹H NMR (600 MHz, DMSO-d₆) δ 12.81 (br. s., 1H), 7.74 (dd, J=1.17, 7.63Hz, 1H), 7.41-7.46 (m, 1H), 7.26-7.34 (m, 2H), 4.61 (br. s., 1H), 3.56(t, J=7.04 Hz, 2H), 3.06 (t, J=7.04 Hz, 2H).

EXAMPLE 67 Intermediate 31 Methyl 2-(2-Hydroxyethyl)benzoate

To crude Intermediate 30 (˜2 g, 12.0 mmol) in anhydrous THF(12 ml) andMeOH (12 ml) under N₂ atmosphere at 0° C. was added TMSCHN₂ (7.8 ml,15.66 mmol) via syringe until a persistent yellowish color was observedand development of gas ceased. The solvent was removed on rotaryevaporator under vacuum to yield crude Intermediate 31 as a colorlessoil.

EXAMPLE 68 Intermediate 32 Methyl 2-(2-(tosyloxy)ethyl)benzoate

To crude Intermediate 31 in anhydrous CHCl₃ (25 ml) under N₂ atmosphereat 0° C. was added TsCl (4.5 g, 24.0 mmol) in CHCl₃ (10 ml) followed byaddition of pyridine (3 ml, 36 mmol) immediately. The reaction waswarmed up to room temperature and stirred for 12 hours, and diluted withwater, and the products extracted with EtOAc. The combined organiclayers were washed with brine, and dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (0-20% EtOAc in hexanes) to yield Intermediate 32 (2.2 g, 58%) as aclear oil.

¹H NMR (600 MHz, CDCl₃) δ 7.88 (dd, J=1.32, 7.78 Hz, 1H), 7.65 (d,J=8.51 Hz, 2H), 7.37-7.46 (m, 1H), 7.28-7.32 (m, 1H), 7.19-7.26 (m, 3H),4.29 (t, J=6.60 Hz, 2H), 3.83 (s, 3H), 3.32 (t, J=6.60 Hz, 2H), 2.42 (s,3H).

EXAMPLE 69 Intermediate 33 Methyl 2-(2-Bromoethyl)benzoate

To Intermediate 32 (1.95 g, 5.84 mmol) in acetone (10 ml) was added LiBr(1.01 g, 11.68 mmol), and the mixture was heated to reflux for 5 hoursunder N₂ atmosphere. The solvent was removed, and the residue dilutedwith water, and the products extracted with CH₂Cl₂. The combined organiclayers were washed with brine, and dried over Na₂SO₄ and concentrated invacuo. The crude Intermediate 33 (1.38 g) was used for next step withoutpurification.

¹H NMR (600 MHz, CDCl₃) δ 7.96 (dd, J=1.47, 7.92 Hz, 1H), 7.44-7.51 (m,1H), 7.28-7.37 (m, 2H), 3.91 (s, 3H), 3.64 (t, J=7.34 Hz, 2H), 3.51 (t,J=7.34 Hz, 2H).

EXAMPLE 70 Intermediate 34 Methyl2-(2-(4-Chloro-2-nitrophenoxy)ethyl)benzoate

To a solution of 4-chloro-2-nitrophenol (985 mg, 5.68 mmol) in DMF (10ml) was added crude Intermediate 33 (1.38 g, 5.68 mmol) and K₂CO₃ (3.9g, 28.4 mmol) and the reaction was stirred at 90° C. for 16 hours,diluted with H₂O, and the resulting solution was extracted with EtOAcand washed with brine, dried over Na₂SO₄ and concentrated in vacuo,followed by MPLC purification to yield Intermediate 34 (520 mg, 27% for2 steps).

¹H NMR (600 MHz, CDCl₃) δ 7.96 (dd, J=1.17, 7.92 Hz, 1H), 7.79 (d,J=2.64 Hz, 1H), 7.47-7.53 (m, 1H), 7.41-7.46 (m, 2H), 7.33 (td, J=1.17,7.63 Hz, 1H), 7.07 (d, J=8.80 Hz, 1H), 4.39 (t, J=6.31 Hz, 2H), 3.91 (s,3H), 3.49 (t, J=6.31 Hz, 2H).

EXAMPLE 71 Intermediate 35 Methyl2-(2-(2-Amino-4-chlorophenoxy)ethyl)benzoate

To a solution Intermediate 34 (685 mg, 2.04 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (3.3 g, 51 mmol). Thesuspension was stirred at room temperature for 1 hour and was filtered,the filtrate was extracted with EtOAc (×2). The combined organic layerswere washed with brine, and dried over Na₂SO₄, and concentrated invacuo. The crude Intermediate 35 (557 mg, 89%) was used in the nextreaction without further purification.

¹H NMR (600 MHz, CDCl₃) δ 7.94 (dd, J=0.88, 7.63 Hz, 1H), 7.47 (dd,J=1.17, 7.63 Hz, 1H), 7.36 (d, J=7.63 Hz, 1H), 7.32 (td, J=1.17, 7.63Hz, 1H), 6.69 (d, J=8.51 Hz, 1H), 6.65 (d, J=2.35 Hz, 1H), 6.60-6.64 (m,1H), 4.23 (t, J=6.60 Hz, 2H), 3.90 (s, 3H), 3.79 (br. s., 2H), 3.49 (t,J=6.46 Hz, 2H).

EXAMPLE 72 Compound 37 Methyl2-(2-{2-[(1-Benzofuran-2-ylsulfonyl)amino]-4chlorophenoxy}ethyl)benzoate

To Intermediate 35 (555 mg, 1.82 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (393 mg, 1.82 mmol) and the reaction wasstirred at 100° C. for 16 hours and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Compound 37 (634 mg, 88%).

¹H NMR (600 MHz, CDCl₃) δ 7.97 (dd, J=1.17, 7.92 Hz, 1H), 7.60-7.64 (m,1H), 7.55 (d, J=2.64 Hz, 1H), 7.53 (td, J=1.47, 7.48 Hz, 1H), 7.40-7.48(m, 3H), 7.35 (td, J=1.17, 7.63 Hz, 1H), 7.28-7.32 (m, 2H), 6.95 (dd,J=2.49, 8.66 Hz, 1H), 6.69 (d, J=8.80 Hz, 1H), 4.13 (t, J=6.46 Hz, 2H),3.92 (s, 3H), 3.36 (t, J=6.31 Hz, 2H).

EXAMPLE 73 Compound 382-(2-{2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}ethyl)benzoicAcid

To Compound 37 (505 mg, 1.04 mmol) in MeOH (30 ml) was added 5M NaOH (2ml) and the reaction was stirred at room temperature for 16 hours. Themixture was acidified with 10% HCl, and extracted with EtOAc (×2). Thecombined organic layers were washed with brine, and dried over Na₂SO₄,and concentrated in vacuo. The crude product was recrystallized fromminimal MeOH and CH₂Cl₂ to yield Compound 38 (454 mg, 93%).

¹H NMR (600 MHz, CDCl₃) δ 8.07 (d, J=7.92 Hz, 1H), 7.67 (br. s., 1H),7.61 (d, J=7.92 Hz, 1H), 7.55 (td, J=1.17, 7.48 Hz, 1H), 7.52 (d, J=2.35Hz, 1H), 7.35-7.46 (m, 3H), 7.27-7.35 (m, 3H), 6.93 (dd, J=2.49, 8.66Hz, 1H), 6.65 (d, J=8.80 Hz, 1H), 4.10 (t, J=6.46 Hz, 2H), 3.45 (t,J=6.02 Hz, 2H).

Biological Data

HEK-Gqi5 cells stably expressing CCR2 were cultured in DMEM highglucose, 10% FBS, 1% PSA, 400 pg/ml geneticin and 50 μg/ml hygromycin.Appropriate positive control chemokines (MCP-1, MIP1A or RANTES) wasused as the positive control agonist for screening compound-inducedcalcium activity assayed on the FLIPR^(Tetra). The drug plates wereprepared in 384-well microplates using the EP3 and the MuItiPROBErobotic liquid handling systems. Compounds were synthesized and testedfor CCR2 activity.

Table 1 shows activity: CCR2 receptor (IC₅₀) nM

CCR2 CCR2 ANTAG- IC50 ONISM IUPAC Name (nM) (%)N-(5-chloro-2-methoxyphenyl)-1-benzofuran-2- 512 97 sulfonamideN-(5-chloro-2-methylphenyl)-1-benzofuran-2- 359 84 sulfonamideN-[5-chloro-2-(trifluoromethoxy)phenyl]-1- 195 95benzofuran-2-sulfonamide methyl 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-1376 95 chlorobenzoate N-(5-chloro-2-ethoxyphenyl)-1-benzofuran-2- 166273 sulfonamide N-(5-chloro-2-ethynylphenyl)-1-benzofuran-2- 117 93sulfonamide N-{5-chloro-2-[(4-oxopiperidin-1- 110 93yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamideN-[5-chloro-2-(morpholin-4-ylcarbonyl)phenyl]- 569 841-benzofuran-2-sulfonamide N-{5-chloro-2-[(2-methylpyridin-3- 365 96yl)oxy]phenyl}-1-benzofuran-2-sulfonamide methyl2-{2-[(1-benzofuran-2-ylsulfonyl)amino]- 1018 984-chlorophenoxy}benzoate 2-{2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 6097 chlorophenoxy}benzoic acid N-[5-chloro-2-(phenylsulfanyl)phenyl]-1-124 90 benzofuran-2-sulfonamide N-[5-chloro-2-(phenylsulfonyl)phenyl]-1-1971 78 benzofuran-2-sulfonamideN-[5-chloro-2-(phenylsulfinyl)phenyl]-1- 6 105 benzofuran-2-sulfonamide2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chloro- 328 95 N-phenylbenzamideN-(5-chloro-2-cyanophenyl)-1-benzofuran-2- 409 102 sulfonamideN-[5-chloro-2-(phenylacetyl)phenyl]-1- 183 79 benzofuran-2-sulfonamideN-{5-chloro-2-[(1Z)-N-methoxy-2- nd 76phenylethanimidoyl]phenyl}-1-benzofuran-2- sulfonamideN-{5-chloro-2-[(1Z)-N-hydroxy-2- nd 72phenylethanimidoyl]phenyl}-1-benzofuran-2- sulfonamideN-[2-(benzyloxy)-5-chlorophenyl]-1-benzofuran- 1629 87 2-sulfonamideN-[5-chloro-2-(phenylethynyl)phenyl]-1- nd 30 benzofuran-2-sulfonamideN-[5-chloro-2-(2-phenylethyl)phenyl]-1- nd 84 benzofuran-2-sulfonamideN-[5-methyl-2-(phenylsulfanyl)phenyl]-1- nd 41 benzofuran-2-sulfonamideN-[5-methyl-2-(phenylsulfinyl)phenyl]-1- 2875 92benzofuran-2-sulfonamide N-[5-methyl-2-(phenylsulfonyl)phenyl]-1- nd 38benzofuran-2-sulfonamide N-[5-fluoro-2-(phenylsulfanyl)phenyl]-1- nd 74benzofuran-2-sulfonamide N-[5-fluoro-2-(phenylsulfinyl)phenyl]-1- 317 91benzofuran-2-sulfonamide N-[5-fluoro-2-(phenylsulfonyl)phenyl]-1- 261882 benzofuran-2-sulfonamide 2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-27 99 chlorophenoxy}methyl)benzoic acid

What is claimed is:
 1. A compound represented by Formula I, itsindividual enantiomers, individual diastereoisomers, individualtautomers or a pharmaceutically acceptable salt thereof:

wherein: R¹ to R⁶ are hydrogen; R⁷ is halogen or methyl; R⁸ is hydrogen;R⁹ is O, C(O), S, S(O), S(O)₂ or —C(═NOR¹⁶)—; a is 0 or 1; R¹¹ isselected from the group consisting of: -Me, —OMe, —C≡CH,

 -Ph, —NHPh, —CN, —CH₂Ph, —C≡CPh, —CH₂CH₂Ph, —CH═CHPh,

R¹⁶ is hydrogen or methyl; X is CH; R¹⁸ is hydrogen.
 2. A compoundaccording to claim 1 selected from the group consisting of:N-(5-chloro-2-methylphenyl)-1-benzofuran-2-sulfonamide; methyl2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorobenzoate;N-(5-chloro-2-ethynylphenyl)-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(4-oxopiperidin-1-yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(morpholin-4-ylcarbonyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chloro-N-phenylbenzamide;N-(5-chloro-2-cyanophenyl)-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylacetyl)phenyl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(1Z)-N-methoxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(1Z)-N-hydroxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylethynyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(2-phenylethyl)phenyl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(Z)-2-phenylethenyl]phenyl}-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicacid;3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicacid; and4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicacid.
 3. A pharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable adjuvant, diluent or carrier.
 4. Apharmaceutical composition according to claim 3 wherein the compound isselected from: N-(5-chloro-2-methylphenyl)-1-benzofuran-2-sulfonamide;methyl 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorobenzoate;N-(5-chloro-2-ethynylphenyl)-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(4-oxopiperidin-1-yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(morpholin-4-ylcarbonyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chloro-N-phenylbenzamide;N-(5-chloro-2-cyanophenyl)-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylacetyl)phenyl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(1Z)-N-methoxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(1Z)-N-hydroxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylethynyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(2-phenylethyl)phenyl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(Z)-2-phenylethenyl]phenyl}-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicacid;3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicacid; and4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoicacid.